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EC number: 257-913-4
CAS number: 52434-90-9
The purpose of the present Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD Guideline 422) in Wistar rats administered by oral gavage was to determine the possible health hazards likely to arise from repeated exposure to AP 729 over a relatively limited period of time. Further, this study provides initial information on possible effects of the test item on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of the conceptus and parturition. The present study also provides information on reversibility, persistence or delayed occurrence of systemic toxic effects, following 14 days post treatment.
The test item was weighed and suspended in vehicle (0.5% Sodium carboxy methyl cellulose with 0.1% Tween 80 in Milli-Q water) and administered at the graduated dose levels of 100, 300 and 1000 mg/kg/day for low dose (G2), mid dose (G3) and high dose (G4)/high dose recovery (G4R) group rats, respectively. The rats in the vehicle control (G1)/vehicle control recovery (G1R) groups received vehicle alone. The dose volume administered was an equivolume of 10 mL/kg. Each main group (G1, G2, G3, G4) in the experiment comprised 10 male and 10 female rats while each recovery group (G1R and G4R) comprised 5 male and 5 female rats.
The dose formulations were administered once daily to a specific group of rats for two weeks prior to mating, during mating and post-mating periods for males, during pregnancy and up to Lactation Day (LD) 13 for females.
The homogeneity and stability of the test item in the vehicle were established before start of treatment at 1 and 100 mg/mL concentrations. Based on the results, the test item was stable in the vehicle up to 48 hours when stored at room temperature.
During the conduct of this study, the prepared dose formulations were analysed for test item concentration prior to dosing on day 1 and during second month (day 46) of the treatment period. The results were considered acceptable, as the mean percent recovery was in the range 70% to 120% at each dose level and %RSD at each dose level was less than 20%.
All rats were observed for clinical signs once daily. Body weight was recorded prior to the start of treatment on day 1 and at weekly intervals thereafter. The body weights were also recorded at termination. Food consumption was recorded at weekly intervals except during the cohabitation period. After confirmation of mating by vaginal smear, the dams were weighed on presumed Gestation Days (GDs) 0, 7, 14 and 20 and the food consumption was recorded on GD 7, 14 and 20. The littered dams were then weighed on LDs 0, 4 and 13 and the food consumption was recorded on LDs 0, 4 and 13.
The number, survival and mortality of pups were observed during the lactation period. The body weight and ano-genital distance of each live pup was measured on LD 0. The size of each litter was adjusted by eliminating extra pups by random selection on LD 4, after recording the body weight of each live pup. After standardization, the individual pup body weight was recorded on LD 13. All the surviving male pups were examined for the appearance of nipples/areolae on LD 13.
Neurological examinations (Functional Observation Battery tests, FOB) were conducted for randomly selected 5 females of each main group on LD 13, for randomly selected 5 males of each main group on treatment day 46 and towards the end of recovery period (day 66) for all the recovery group animals.
Laboratory investigations such as haematology, coagulation, clinical chemistry and urinalysis were performed on randomly selected 5 parental males and 5 parental females from each main group at the end of the two weeks pre-mating period, and towards the end of the recovery period for all the animals of the recovery groups, after overnight fasting. Thyroxine 4 (T4) and Thyroid Stimulating Hormone (TSH) analysis were performed in all main groups males at termination, in all dams on LD 13 and from available pups on LD 4 and 13.
At sacrifice, the parental males (day 50), parental females (LD 14) and the recovery animals (day 67) were subjected to detailed necropsy after overnight fasting (water allowed) and tissues/organs were collected. The pups were sacrificed on LD 13 after examining the external genitals for signs of altered development.Histopathology examination was carried out on the preserved organs (including reproductive organs) from randomly selected 5 males and 5 females in the control and high dose groups and on all gross lesions. Histopathological examination of testes included a qualitative assessment of stages of spermatogenesis. As there were no test item-related changes in the examined organs of high dose animals, tissues from remaining animals (lower dose group and recovery dose group animals) were not subjected for evaluation. Thyroids were examined from all adult males and females and from one randomly selected male and one randomly selected female pup per litter on LD 13.
Under the adopted experimental conditions, the following results were obtained:
Clinical signs and Mortality: There were no treatment related clinical signs observed at any of the doses tested. There were no abnormalities observed in pups. There were no mortalities observed during the treatment at all the tested doses. An isolated incident of mortality was observed in a G3 group female (Rab9323) just prior to necropsy on lactation day 14. The animal was normal during morning observation and the cause of death could not be determined based on gross/microscopic evaluation and was considered an incidental finding.
Functional Observation Battery: No treatment-related neurological abnormalities were observed at any of the doses tested.
Body weights: The mean body weights and body weight gains were unaffected by the treatment at all the tested doses in both sexes.
Food consumption: Treatment did not affect the food consumption at any of the tested doses in either sex.
Maternal body weights and food consumption: The maternal body weight and food consumption during gestation and lactation periods were unaffected by the treatment at all the tested doses.
Fertility parameters: Treatment had no effect on the pre-coital interval, gestation length, oestrous cycle length. The mating and fertility parameters in both sexes were unaffected by the treatment.
Litter parameters: There were no treatment-related effects on the uterine/implantation data, mean litter size and mean viable litter size. There were no external abnormalities in live or dead pups in any of the groups. No treatment-related changes in the ano-genital distance, ano-genital ratio, pup body weights were observed at any of the doses tested when compared to the control. The male pups did not exhibit areola/nipple retention on LD 13 at any of the doses tested.
Haematology, Coagulation, Clinical chemistry and Urine Parameters: No test item-related changes were observed in the haematology, coagulation, clinical chemistry and urine parameters at all the doses tested in both sexes.
Hormone analysis: The thyroid stimulating hormone (TSH) and thyroxine (T4) levels in adult rats and pups remained unaffected by test item administration.
Terminal fasting body weights, organ weights and its ratios: There were no test item-related changes in terminal fasting body weights and organ weights at all dose levels tested in adult males and females. Pups body weights and lactation day 13 thyroid weights were unaffected by the treatment.
Gross and histopathology: There were no test item-related gross lesions observed in both the sexes. There were no developmental and non-developmental gross findings noted in male or female pups. Microscopically, there were no test item-related changes in both adult males and females. Qualitative assessment of stages of spermatogenesis did not reveal any test item-related changes. There were no test item-related microscopic changes in thyroid glands of pups. The cause of death of dead female rat (G3F-Rab9323) could not be determined based on gross and microscopic evaluation findings.
As there were no treatment related effects on systemic, reproduction, and fertility parameters and on F1 generation pups up to and including the highest dose tested of 1000 mg/kg/day, the No Observed Adverse Effect Level (NOAEL) for Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test by oral gavage in Wistar rats for the test item AP 729 is determined to be 1000 mg/kg/day under the adopted test conditions and doses tested.
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